Wnt/β-catenin通路维持肿瘤干细胞表型并增强DNA修复介导骨肉瘤放疗抵抗的机制研究

Osteosarcoma is generally radiotherapy resistant but the mechanism is not well studied. Our previous study showed parathyroid hormone (PTH) efficiently promoted radio-resistance of rat osteosarcoma cell line UMR 106-1 by up-regulating Ku70 and enhancing DNA repair. Our machinery investigation further found this radio-resistance pathway was totally Wnt/β-catenin-dependent. However, ①there is still controversy regarding the status of Wnt/β-catenin in human osteosarcoma cells and ②the role of Ku70 in osteosarcoma radio-resistance is uncertain. And，high Wnt signalling activity is reported to increase stemness and radio-resistance of tumor stem cells (TSCs) in other cancers. To support this observation, our data also indicated progenitors were more tolerable to radiation than non-progenitors. ③But the role of TSCs in radio-resistance of osteosarcoma and its association with Wnt signaling is not confirmed. Here, we are trying to establish an osteosarcoma cell model with stable radio-resistance, which is tend to uncover the causal relationship among Wnt pathway, radio-resistance and TSCs phenotype in osteosarcoma. Also, the findings may lead to development of Wnt signaling and TSCs as a novel clinical therapeutic target for improving radiotherapy-sensitivity of osteosarcoma.

目前已知骨肉瘤是普遍放疗抵抗的，但具体机制未明。前期研究中我们报道， PTH上调Ku70蛋白促进DNA修复并介导大鼠骨肉瘤UMR 106-1细胞放疗抵抗主要通过Wnt/β-catenin通路。但①Wnt/β-catenin通路在人骨肉瘤组织的表达状态尚有争议；② Ku70蛋白在人骨肉瘤放疗抵抗中的作用尚未阐明。另一方面，文献报道Wnt/β-catenin通路介导肿瘤干细胞表型与肿瘤放疗抵抗密切相关，我们的前期实验也证明了这一点：具多向分化能力的前体细胞要比分化细胞更具抗凋亡能力。③但骨肉瘤干细胞是否介导放疗抵抗？与Wnt/β-catenin通路有何关系？目前尚不明确。故此，本项目利用梯度剂量的X射线辐射筛选并建立放疗抵抗的骨肉瘤模型，采用体内体外系统，深入探讨Wnt/β-catenin通路维持肿瘤干细胞表型、调控DNA修复并介导肿瘤放疗抵抗的机理，为提高骨肉瘤的放疗疗效提供新的靶点。